Derivatives of Carboxylic Acid

acid chloride

carboxylate

nitrile

amide

ester

acid anhydride

Nomenclature of Acid Halides

IUPAC: alkanoic acid → alkanoyl halide

Common: alkanic acid → alkanyl halide

I: 3-aminopropanoyl chloride

c: b-aminopropionyl chloride

I: 4-nitropentanoyl chloride

c: g-nitrovaleryl chloride

I: hexanedioyl chloride

c: adipoyl chloride

Rings: (IUPAC only): ringcarbonyl halide

I: 3-cylcopentenecarbonyl chloride

I: benzenecarbonyl bromide

c: benzoyl bromide

Nomenclature of Acid

Anhydrides

Acid anhydrides are prepared by dehydrating carboxylic acids

acetic anhydride

ethanoic acid ethanoic anhydride

I: benzenecarboxylic anhydride

c: benzoic andhydride I: butanedioic acid

c: succinic acid

I: butanedioic anhydride

c: succinic anhydride

Some unsymmetrical anhydrides

I: cis-butenedioic

anhydride

I: benzoic methanoic anhydride

c: benzoic formic anhydride

I: ethanoic methanoic

anhydride

c: acetic formic anhydride

Nomenclature of Esters Esters occur when carboxylic

acids react with alcohols

I: methyl ethanoate

c: methyl acetate

I: phenyl methanoate

c: phenyl formate

I: t-butyl benzenecarboxylate

c: t-butyl benzoate

I: isobutyl

cyclobutanecarboxylate

c: none

I: cyclobutyl 2-

methylpropanoate c: cyclobutyl a-

methylpropionate

I: dimethyl ethanedioate

c: dimethyl oxalate

Cyclic Esters

Reaction of -OH and -COOH on same molecule

produces a cyclic ester, lactone.

To name, add word lactone to the IUPAC acid name or

replace the -ic acid of common name with -olactone.

4-hydroxy-2-methylpentanoic acid lactone

-methyl- -valerolactone

Amides

Product of the reaction of a carboxylic

acid and ammonia or an amine.

Not basic because the lone pair on

nitrogen is delocalized by resonance.

Classes of Amides

1 amide has one C-N bond (two N-H).

2 amide or N-substituted amide has

two C-N bonds (one N-H).

3 amide or N,N-disubstituted amide

has three C-N bonds (no N-H).

=>

Naming Amides

For 1 amide, drop -ic or -oic acid from

the carboxylic acid name, add -amide.

For 2 and 3 amides, the alkyl groups

bonded to nitrogen are named with N- to

indicate their position.

N-ethyl-N,2-dimethylpropanamide

N-ethyl-N-methylisobutyramide

Cyclic Amides

Reaction of -NH2 and -COOH on same

molecule produces a cyclic amide, lactam.

To name, add word lactam to the IUPAC

acid name or replace the -ic acid of

common name with -olactam.

4-aminopentanoic acid lactam

-valerolactam

Relative Reactivity of Carbonyl Carbons

Nucleophiles (electron donors), like OH-, bond with the sp2 hybridized

carbonyl carbon.

The order of reactivity is shown.

Nitriles

-C≡N can be hydrolyzed to carboxylic

acid, so nitriles are acid derivatives.

Nitrogen is sp hybridized, lone pair tightly

held, so not very basic. (pKb about 24).

Naming Nitriles

For IUPAC names, add -nitrile to the

alkane name.

Common names come from the

carboxylic acid. Replace -ic acid with -

onitrile.

5-bromohexanenitrile

-bromocapronitrile

Cyclohexanecarbonitrile

=>

Acid Halides

More reactive than acids; the halogen

withdraws e- density from carbonyl.

Named by replacing -ic acid with -yl

halide.

benzoyl chloride

3-bromobutanoyl bromide

-bromobutyryl bromide

=>

Acid Anhydrides

Two molecules of acid combine with the loss of

water to form the anhydride.

Anhydrides are more reactive than acids, but

less reactive than acid chlorides.

A carboxylate ion is the leaving group in

nucleophilic acyl substitution reactions.

Naming Anhydrides

The word acid is replaced with anhydride.

For a mixed anhydride, name both acids.

Diacids may form anhydrides if a 5- or 6-

membered ring is the product.

ethanoic anhydride

acetic anhydride 1,2-benzenedicarboxylic anhydride

phthalic anhydride

Multifunctional Compounds

The functional group with the highest

priority determines the parent name.

Acid > ester > amide > nitrile > aldehyde

> ketone > alcohol > amine > alkene >

alkyne.

ethyl o-cyanobenzoate

Boiling Points

Even 3º amides have

strong attractions.

Melting Points

Amides have very high melting points.

Melting points increase with increasing

number of N-H bonds.

m.p. -61ºC m.p. 28ºC m.p. 79ºC

Solubility

Acid chlorides and anhydrides are too reactive to be used with water or alcohol.

Esters, 3º amides, and nitriles are good polar aprotic solvents.

Solvents commonly used in organic reactions:

Ethyl acetate

Dimethylformamide (DMF)

Acetonitrile =>

IR Spectroscopy

1H NMR Spectroscopy

13C NMR Spectroscopy

Interconversion of

Acid Derivatives Nucleophile adds to the carbonyl to form

a tetrahedral intermediate.

Leaving group leaves and C=O

regenerates.

Reactivity

Reactivity decreases as leaving group

becomes more basic.

Interconversion of Derivatives

More reactive

derivatives can be

converted to less

reactive derivatives.

Acid Chloride to Anhydride

Acid or carboxylate ion attacks the C=O.

Tetrahedral intermediate forms.

Chloride ion leaves, C=O is restored, H+

is abstracted.

=>

Acid Chloride to Ester

Alcohol attacks the C=O.

Tetrahedral intermediate forms.

Chloride ion leaves, C=O is restored, H+

is abstracted.

=>

Acid Chloride to Amide

Ammonia yields a 1º amide

A 1º amine yields a 2º amide

A 2º amine yields a 3º amide

Anhydride to Ester

Alcohol attacks one C=O of anhydride.

Tetrahedral intermediate forms.

Carboxylate ion leaves, C=O is restored,

H+ is abstracted.

=>

Anhydride to Amide

Ammonia yields a 1 amide

A 1 amine yields a 2 amide

A 2 amine yields a 3 amide

Ester to Amide

Nucleophile must be NH3 or 1 amine.

Prolonged heating required.

Leaving Groups

A strong base is not usually a leaving

group unless it’s in an exothermic step.

Transesterification

One alkoxy group can be replaced by

another with acid or base catalyst.

Use large excess of preferred alcohol.

Hydrolysis of Acid

Chlorides and Anhydrides Hydrolysis occurs quickly, even in moist

air with no acid or base catalyst.

Reagents must be protected from

moisture.

Acid Hydrolysis of Esters

Reverse of Fischer esterification.

Reaches equilibrium.

Use a large excess of water.

Saponification

Base-catalyzed hydrolysis of ester.

“Saponification” means “soap-making.”

Soaps are made by heating NaOH with a

fat (triester of glycerol) to produce the

sodium salt of a fatty acid - a soap.

One example of a soap is sodium

stearate, Na+ -OOC(CH2)16CH3.

=>

Hydrolysis of Amides

Prolonged heating in 6 M HCl or 40%

aqueous NaOH is required.

Hydrolysis of Nitriles

Under mild conditions, nitriles hydrolyze

to an amide.

Heating with aqueous acid or base will

hydrolyze a nitrile to an acid.

Reduction to Alcohols

Lithium aluminum hydride reduces acids,

acid chlorides, and esters to primary

alcohols.

Reduction to Aldehydes

Acid chlorides will react with a weaker

reducing agent to yield an aldehyde.

Reduction to Amines

Lithium aluminum hydride reduces amides

and nitriles to amines.

Nitriles and 1 amides reduce to 1

amines.

A 2 amide reduces to a 2 amine.

A 3 amide reduces to a 3 amine.

Organometallic Reagents

Grignard reagents and organolithium

reagents add twice to acid chlorides and

esters to give alcohols after protonation.

Grignard Reagents

and Nitriles A Grignard reagent or organolithium

reagent attacks the cyano group to yield

an imine which is hydrolyzed to a ketone.

Acid Chloride Synthesis

Use thionyl chloride, SOCl2, or oxalyl

chloride, (COCl)2.

Other products are gases.

Acid Chloride Reactions (1)

acid

ester

amide

acid anhydride

Acid Chloride Reactions (2)

3° alcohol

ketone

1° alcohol

aldehyde

acylbenzene

Industrial Synthesis

of Acetic Anhydride Four billion pounds/year produced.

Use high heat (750°C) and triethyl

phosphate catalyst to produce ketene.

Lab Synthesis

of Anhydrides React acid chloride with carboxylic acid

or carboxylate ion.

Heat dicarboxylic acids to form cyclic anhydrides.

Anhydride Reactions

Anhydride vs. Acid Chloride

Acetic anhydride is cheaper, gives a better

yield than acetyl chloride.

Use acetic formic anhydride to produce

formate esters and formamides.

Use cyclic anhydrides to produce

a difunctional molecule.

Synthesis of Esters

Reactions of Esters

Lactones

Formation favored for five- and six-

membered rings.

For larger rings, remove water to shift equilibrium

toward products

Synthesis of Amides

Reactions of Amides

acid and amine

amine

1° amine

nitrile

Lactam Formation

Five- and six-membered rings can be

formed by heating - and -amino acids.

Smaller or larger rings do not form readily.

-Lactams

Highly reactive, 4-membered ring.

Found in antibiotics isolated from fungi.

Synthesis of Nitriles

Reactions of Nitriles

Thioesters

More reactive than esters because:

◦ -S-R is a better leaving group than -O-R

◦ Resonance overlap is not as effective.

Carbonic Acid Esters

CO2 in water contains some H2CO3.

Diesters are stable.

Synthesized from phosgene.

Urea and Urethanes

Urea is the diamide of carbonic acid.

Urethanes are esters of a monoamide of

carbonic acid.

Polymers

Polycarbonates are long-chain esters of

carbonic acid.

Polyurethanes are formed when a diol

reacts with a diisocyanate.